Dihydrolipoic acid as an ophthalmological agent to suppress intolerance reactions in the area between implants and living body tissue

ABSTRACT

Pharmaceutical compositions comprising dihydrolipoic acid or physiologically acceptable salts thereof are disclosed for the treatment of eye diseases and intolerance reactions in the area between implants and endoprostheses, in particular ophthalmological implants and endoprostheses with living body tissue.

This application claims benefit of International applicationPCT/EP94/011110, filed Apr. 11, 1994.

BACKGROUND OF THE INVENTION

The present invention relates to the use of dihydrolipoic acid(6,8-dimercapto-octanic acid) in diseases of the eye and in intolerancereactions of the eye with implants, such as for example vitreous bodyand lens replacement material. Dihydrolipoic acid may also be used inthe event of intolerance reactions of other body tissues withendoprostheses and implants.

Under physiological conditions, dihydrolipoic acid, the reduced form ofα-lipoic acid, is involved in the regulation of the cellular redoxstate. Oxidation reactions due to certain highly reactive oxygencompounds have been found to trigger various symptoms through damage tocells and tissues.

Equilibria generally tend to exist intracellularly and extracellularlybetween the formation of reactive oxygen species and theirrequirement-oriented concentration regulation due to a balancedantioxidative system. This regulation system involves low molecularcompounds such as vitamin A (retinol), vitamin C (ascorbic acid),vitamin E (α-tocopherol), uric acid and glutathion as well as specialenzymes with antioxidative function. If this system is weakened orchronically overloaded, it should be augmented from outside by addedantioxidants to achieve continuous protection against damage.

Blockage of the coenzyme α-lipoic acid is known to lead to impairedoxidative metabolism.

DE-A-40 35 456 discloses the use of dihydrolipoic acid for combatingretroviruses, in particular the HIV virus. It is also possible to use acombination with another anti-retrovirally acting substance.

DE-A-40 02 706 describes dihydrolipoic acid as having an analgesic,anti-inflammatory and cytoprotective effect.

Furthermore, the radical-capturing and reducing effect of dihydrolipoicacid is known from the report published by universimed Verlag 1993 of asymposium (The status of antioxidants in the treatment of Diabetesmellitus). Kahler et al. report that dihydrolipoic acid displays aquench effect against peroxyl and superoxide radicals in cytosol andhydrophobic domains. Packer shows in connection with oxidativeprotective effect that a synergistic effect exists between vitamin Eand/or vitamin C and dihydrolipoic acid. On the basis of modelreactions, Burkart et al. raise the question as to whether dihydrolipoicacid should be used to suppress inflammatory processes in Type Idiabetes. Elstner reports that the photooxidation of crystallinesoccurring due to radiation can be prevented by dihydrolipoic acid.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the five main components of a lens homogenate obtained bymeans of FPLC filtration and the molecular weights allocated accordingto the retention time.

FIG. 2 shows results of an oxidation of SH-groups in a lens homogenateby exposed riboflavin and the influence of dihydrolipoic acid.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide pharmaceuticalswhich are suitable for the treatment or prophylaxis of diseases of theeye and for the suppression and prevention of intolerance reactions inthe area between implants and living body tissue.

This object is solved by using dihydrolipoic acid or its physiologicallyacceptable salts to prepare pharmaceutical compositions for thetreatment of disorders triggered by radicals in living body tissue.

The subordinate claims describe preferred embodiments of the useaccording to the invention.

DETAILED DESCRIPTION OF THE INVENTION

The disorders are in particular diseases of the eye, for examplecataracts, retinopathy or retrolental fibroplasia and intolerancereactions in the area between implants and endoprostheses and livingbody tissue. Ophthalmological implants are particularly preferred.Treatment may already be prophylactic in order in particular to avoid orreduce intolerance reactions in the area between implants orendoprostheses and living body tissue.

Dihydrolipoic acid is able to exert a favourable influence on thepathobiochemical processes caused in these disease processes by theappearance of reactive radicals.

It is possible that extensive exposure of the lens suffices to causeradiation-triggered chemical processes in which reactive, in particularoxygen-containing radicals are formed. The stress situation in the eyeis very great since the lens also contains substances such as riboflavin(vitamin B) and N-formylkynurenine which, being light sensitisers,trigger radiation-related reactions. As a result thereof, discolorationsand covalent protein cross-linkage occur in the lens during ageing, butintensified in the case of cataractogenesis (pathological clouding dueto grey cataract). In healthy lenses the proportion of antioxidants suchas ascorbate and glutathione and protecting enzymes such as glutathioneperoxidase is markedly higher than in cataract lenses. Here, a higherproportion of hydrogen peroxide is also encountered. Furthermore, if acataract is present there is also continuous oxidation of cysteine andmethionine in the lens.

Similar radical-mediated protein degradations as occur in the lenstissue also occur in the vitreous body of the eye in various metabolicdiseases, such as Diabetes mellitus, and also in age and on the basis ofvarious causes, some of which are as yet unknown. In the case ofpremature and newly born babies exposed to elevated oxygen partialpressures in an incubator because of disturbed maturation of the lung,oxidative stress leads to the development of so-called retrolentalfibroplasia.

All these processes not only change the protein structure and thus thefibrous texture of the vitreous body, and thus the light permeabilitythereof, but can also induce other pathological changes and thusretinopathy due to the changed traction and pressure conditions at thesurrounding retina and its vessels.

The use of dihydrolipoic acid according to the invention serves for thetreatment of

1. senile cataract, cataract caused by radiation, UV-radioactivity or bythermal radiation,

2. professionally caused, vitamin deficiency-induced cataract,

3. senile- or myopia-induced retinopathy,

4. retrolental fibroplasia.

The incidence of radicals may also be shown when implants andendoprostheses are inserted. These occur due to release or abrasion ofminute metal or plastic species (ions or particles) which are able toinduce foreign body reactions. All these processes may led to delay ordisturbance or impairment of the settling process. Foreign bodygranulomas or projecting connective tissue may form about the implant orendoprosthesis which lead to mechanical, optical, electrical or chemicaland other functional impairments, or the desired function may only bepossible later or only for a limited period as a result hereof. In thecase of subdermal implantation, these processes may also lead tocosmetically disturbing scar formation with subsequent shrinkageprocesses and impaired movement.

The release of implant material is also observed in the case of ocularimplants. The inflammatory foreign body reactions induced hereby mayalso lead to disturbed and delayed settling as well as the formation ofpoorly or not at all light-permeable scar tissue in the area of theimplant and thus, for example, totally or partially prevent the functionthereof in maintaining or improving vision.

The foreign body reactions occurring Intra- and extracellularly thusconstitute a uniform reaction of all body tissues or organs to a foreignbody stimulus. It is known from various publications that onlyquantitative differences exist here.

The testing of the bioavailability of implants and endoprostheses, forexample of ophthalmological implants, is effected in animal experimentsin which the implants are introduced into the subcutaneous tissue or byintraocular implantation. It has been found that administration ofdihydrolipoic acid in the form of a pharmaceutical composition duringbiotolerance testing is able to suppress or markedly reduce intolerancereactions. Because of the similar disturbances in the case of implantsin the subcutaneous tissue, in intramuscular implantation and inintraocular implantation, use according to the invention is generallysuitable for the treatment of acute diseases and also for prophylaxis inpossible intolerance reactions of implants and endoprostheses.

An additional therapy possibility is thus use in vitreous bodyreplacement (endoprostheses), anterior chamber lens replacement,endoprostheses and implants in general.

The effect of dihydrolipoic acid has been shown by investigating theconsequences of UV radiation on a homogenous extract of bovine eyelenses. During this procedure the molecular weight composition and theproportion of free SH groups in the extract were determined. Inphotochemically triggered, degenerative processes in eye lenses themolecular weight composition changes to higher aggregates whichdecreases the proportion of free SH-groups which cause thecross-linkage. Radiation was carried out with and without addedriboflavin and then with increasing concentration of dihydrolipoic acid.

During degranulation, activated leucocytes secrete myeloperoxidase daseinto the phagosome where the myeloperoxidase reacts with H₂ O₂ and Cl⁻to hypochlorous acid HOCl. This is a highly active bactericide andinactivator of numerous enzymes.

EXAMPLES

A. Exposure of extract of bovine eye lenses (lens homogenate LH) anddetermination of the molecular weight composition.

1. Lens homogenate of bovine eyes

Bovine eyes of freshly slaughtered animals were processed in thelaboratory immediately after transport (cooled, physiological NaClsolution (0°-4° C.); duration of transport approx. 30 min.).

The lenses are isolated from bovine bulbi and intermediately stored inphysiological NaCl solution after removing adhering vitreous and ciliarybody residue. The drained weight of the lenses is then determined(plastic sieve). The lenses are homogenised in a mortar (on ice)precooled with a little liquid nitrogen and mixed with cooled,physiological NaCl solution in a ratio of 1 g lens per 1 ml saltsolution. The mixture is then centrifuged for 30 min. at 15000 g and theaqueous supernatant that contains the water-soluble protein proportionis filtered through sterile filters (0.22 um) into brown vials withscrew-top lids (20 ml). Before the vials are closed, the lens homogenateis covered with gaseous nitrogen to keep oxidation reactions due tooxygen in the air as low as possible. The lens homogenate so obtained isstored at -20° C. until used.

2. Determination of the lens homogenate-protein concentration

The Bio-Rad Protein Assay is used for quantitatively recording proteinsin solutions. The assay corresponds to the method described by Bradford(1976) which is based on the shift in the absorption maximum of aphosphoric acid, methanol solution of Comassie Brilliant Blue G 250 of465 nm to 595 nm when this dyestuff binds to protein or amino groups.Bovine serum albumin (BSA) is used as standard protein.

For the assay, 5 ml of the 1:5 diluted dyestuff reagent are mixed with0.1 ml sample solution and the extinction is determined at 595 nm after15 min. incubation at room temperature. 0.1 ml solvent of the protein isused as the test solution in the assay. The colour reagent is subject toageing, particularly in dilute form. For this reason the dilution of thedetermining reagent is always freshly prepared and a new calibrationgradient with BSA is established for each new dilution. The calibrationsolutions contain between 0.1 and 0.8 mg/ml BSA. The photometricallyobtained extinction values are converted on the basis of the calibrationcurve in the form of mg protein per ml lens homogenate. The averageprotein content is 110-130 mg per ml lens homogenate.

3. Riboflavin-catalysed photooxidation of lens proteins

Lens homogenate is exposed together with riboflavin and then examinedusing FPLC (gel filtration). This reveals a change in the molecularweight composition of the lens homogenate as a function of the exposuretime, high molecular weight aggregates increasingly being formed. Thismodel reaction stimulates a possible photodynamic change in lensproteins during the cataractogenesis.

It was now investigated whether dihydrolipoic acid can influence thisphotodynamic damage of the lens homogenate. Dihydrolipoic acid inhibitsthe gel chromatographically detectable change in the lens homogenate LHdue to UV radiation depending on concentration. FIG. 1 reproduces thefive main components of the lens homogenate obtained by means of FPLCfiltration and those of the molecular weights allocated according to theretention time. The peak area obtained after 15 min. exposure withoutriboflavin serves as reference parameter (=100%).

Reagents used:

Lens homogenate 5.74±0.13 mg/ml

Riboflavin 25 um

Dihydrolipoate 0.05-1.00 mM

The batch volume was 2.00 ml; reaction temperature 37° C; reaction timet=15 min; light intensity 30 klux (4 nitrophot bulbs of 500 W each)

B. Exposure of bovine eye lens extract (lens homogenate LH) anddetermination of the oxidation of free thiol groups in the lenshomogenate

1. Determination of free protein sulfydryl groups

This test is based on a method after ELLMAN (1958, 1959) and covers theLH groups available in solution.

Free SH-groups reductively release the strongly yellow-dyed chromogen2-nitro-5-mercaptobenzoate from colourless, disulfidic Ellman's reagentDTNB (5,5'-dithio-bis-2-nitrobenzoic acid, dissolved in methanol)(SEKLAK & LINDSAY, 1968). In so doing, the extinction of this dyestuffat 412 nm correlates linearly with the SH concentration used in therange of 10-100 uM SH. A typical assay is composed as follows:

    ______________________________________                                        Phosphate buffer pH 7.4                                                                     100 mM     (1.00 ml 0.2 M)                                      Test solution 10-100 um SH                                                                             (0.20 ml 0.1-1 mM SH)                                aqua dest     ad 2.00 ml                                                      DTNB          200 uM     (0. 20 ml 2 mM DTNB in                                                        methanol)                                            ______________________________________                                    

The determination reaction is started by adding DTNB and the dyestuffformed is determined photometrically (E_(412nm)) after 30 min at roomtemperature.

2. Oxidation of free thiol groups in the lens homogenate

Lens proteins have a comparatively high concentration of free SH-groups.If lens proteins are exposed to oxidative stress, the SH group decreasecan serve as an indication of the extent of the damage caused. It isexamined whether dihydrolipoic acid can intervene in the oxidationprocesses. Exposed riboflavin serves as oxidative system. Thequantitative recording of the SH-groups occurs using the modified methodafter Ellman.

Fresh lens homogenate has an SH concentration of 2.25±0.12 mM whichdecreases steadily, despite storage at -20° C. and coating withnitrogen. Thus, 1.93±0.05 mM SH are still detectable in the lenshomogenate after 8 weeks' storage, representing a loss of some 14%. TheSH-decrease occurs much more quickly at room temperature: after 24 hoursabout 5-10% have already oxidised after 24 hours. If the SHconcentration is related to the protein content of the lens homogenate,the following absolute values are obtained:

Lens homogenate fresh: 19.60±1.05 umol SH/g protein

Lens homogenate (8 weeks at -20° C.): 16.83±0.44 umol SH/g protein

This test examined to what extent the SH concentration of thephotooxidised lens homogenate changes in this test system and examinedthe effect of the dihydrolipoic acid on this indicator. After 30 minreaction time the dyestuff is quantified at 412 nm. Since riboflavineven absorbs in this range, 0.50 ml from the incubation batch is used asreference in the Ellman test without DTNB. Use of this type of referencealso takes into account the fact that riboflavin even oxidizes in thelight, as expressed in an increasing bleaching of the solution.

In this batch, dihydrolipoic acid impaired determination of the lenshomogenate-SH since this was above all present in the batch above all inhigher concentrations still above 50 uM after 15 min. exposure withriboflavin, i.e. the E_(412nm) values were outside the measuring rangeand it was mainly dihydrolipoic acid that way measured and not lenshomogenate-SH. To be able to nevertheless measure the influence on theSH-groups of the lens homogenate, the batches were gel-filtered throughNAP™-25 columns after incubation in the light, whereby the dihydrolipoicacid was separated from the lens proteins. The approximatelydihydrolipoic acid-free fraction was now used in theEllman-determination and the sulfhydryl content determined. The NAP™-25columns separate in the range of 1 to 5 dkal, i.e. proteins with amolecular weight of over 5 kdal are eluted with the elution agent. Theresult, however, is also that the glutathion of the lens homogenate andsmall SH-containing peptides are separated as well. In addition, thesamples are diluted by the gel filtration, although this is balanced bya higher sample aliquot in the Ellman batch. Dihydrolipoic acid inhibitsSH-group oxidation of the lens proteins in dependence of concentration.

FIG. 2 shows these results of the oxidation of SH-groups in the lenshomogenate by exposed riboflavin and the influence of dihydrolipoicacid.

The SH-loss of the control resulting from gel filtration is 7.1 ±0.4 mM(approx. 15%). Comparing the protein contents before and after gelfiltration, a loss of 0.52±0.06 mg/ml (approx. 18%) is found. If theelution of a standard protein from the NAP™-25 column is checked, ayield of 98.5±3.4% is obtained in the 3.5 ml eluate. This means,however, that the loss of SH or protein of the gel filtered lenshomogenate is provoked by separated low molecular components.

For use according to the invention, dihydrolipoic acid or itsphysiologically acceptable salts are formulated to administrablemedicaments together with conventional auxiliary substances, it alsobeing possible to use the salt formers in excess, i.e. in an amounthigher than equimolar.

For salt formation it is possible to use conventional bases or cationswhich are physiologically acceptable in the salt form. Examples hereofare: acceptable alkaline or alkaline earth metals, ammonium hydroxide,basic amino acids such as arginin and lysin, amines of the formula NR₁R₂ R₃ where the radicals R₁, R₂ and R₃ are the same or different andrepresent hydrogen, C₁ -C₄ -alkyl or C₁ -C₄ oxyalkyl such as mono- anddiethanolamine, 1-amino-2-propanol, 3-amino-1-propanol; alkylenediaminewith one alkylene chain of 2-6 carbon atoms as well as ethylene diamineor hexamethylene tetramine, saturated cyclic amino compounds with 4-6ring carbon atoms such as piperidine, piperazine, pyrrolidine,morpholine; N-methylglucamin, creatine, trometamol.

Dihydrolipoic acid as a pharmaceutical composition may be applied to theskin or mucous membrane or to the inside of the body, for example oral,enteral, pulmonal, nasal, lingual, intravenous, intra-arterial,intracardial, intramuscular, intraperitoneal, intracutaneous,subcutaneous and in the vitreous body or the anterior eye chamber.

Apart from the systemic, oral or parenteral (i.v., i.m., i.c. and s.c.)application of dihydrolipoic acid, the topical application ofdihydrolipoic acid solutions, suspension, emulsions and gels may also becorneally and conjunctivally. In addition, applications of thesubstances is also possible by means of release via a medicamentreservoir localised in the conjunctival sac or subconjuctival, dermal,subdermal, intra-ocular, articular or in other body tissue.

Application may also be by giving the substances in sustained releaseand also non-sustained release form to endoprostheses and implants.

Other antioxidants that may for example be used are sodium sulfite,sodium hydrogen sulfite, sodium metabisulfite, ascorbic acid, ascorbylpalmirate, -myristate, -stearate, gallic acid, gallic acid alkyl ester,butylhydroxyanisol, nordihydroguaiaretic acid, tocopherols andsynergists (substances that bind heavy metals by complex formation, forexample lecithin, ascorbic acid, phosphoric acid, ethylenediaminotetraacetic acid, citrates, tartrates). Addition of thesynergists substantially increases the antioxygenic effect of theantioxidants. Conserving agents that may for example also be used aresorbic acid, p-hydroxybenzoic acid esters (for example lower alkylesters), benzoic acid, sodium benzoate, trichlorisobutyl alcohol,phenol, creosol, benzethonium chloride, chlorohexidine and formalinderivatives.

It is also possible to use polyphenols as additives. Rutin, quercetinand morin or mixtures thereof are particularly suitable.

It is in some cases also appropriate to add preservatives, stabilisers,buffers, masking flavors, sweeteners, dyestuffs, antioxidants andcomplex formers and the like. Complex formers that may for example beused are: chelate formers such as ethylene diamino tetraacetic acid,nitrilotriacetic acid, diethylene triamine pentascetic acid as well assalts thereof.

The complex formers may also be those which contain dihydrolipoic acidin an interstice. Examples hereof are urea, thiourea, cyclodextrins,amylose.

To stabilize the active substance molecule the pharmaceuticalcomposition is preferably adjusted to a pH range of approx. 6-9 withphysiologically acceptable bases or buffers. In general as neutral orweakly basic (up to pH 8) a pH value as possible is preferred.

In the case of parenteral formulations these are in particular sterilean or sterilized formulations.

Examples of carriers and auxiliary substances are gelatins, naturalsugars such as cane sugar or lactose, lecithin, pectin, starch (e.g.corn starch or amylose), cyclodextrins and cyclodextrin derivatives,dextran, polyvinylpyrrolidone, polyvinyl acetate, gum arabic, alginicacid, tylose, lycopodium, silicic acid (e.g. colloidal), cellulose,cellulose derivatives (e.g. cellulose ethers in which the cellulosehydroxy groups are partially etherified with lower saturated aliphaticalcohols and/or lower saturated aliphatic oxyalcohols, e.g.,methyloxypropyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methyl cellulose phthalate); fatty acids aswell as magnesium, calcium or aluminium salts of fatty acids with 12-22carbon atoms, in particular saturated (e.g. stearates), emulsifiers,oils and fats, in particular vegetable (e.g. peanut oil, castor oil,olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil,sunflower seed oil, cod liver oil, in each case also hydrated); glycerolesters and polyglycerol esters of saturated fatty acids C₁₂ H₂₄ O₂ toC₁₈ H₃₆ O₂ and mixtures thereof, where the glycerol hydroxy groups aretotally or also only partially esterified (e.g. mono-, di- andtriglycerides); pharmaceutically acceptable mono- or multivalentalcohols and polyglycols such as polyethylene glycols (molecular weightrange for example 300 to 1500) as well as derivatives thereof,polyethylene oxide, esters of aliphatic saturated or unsaturated fattyacids (2-22 carbon atoms, in particular 10-18 carbon atoms) withmonovalent aliphatic alcohols (1-20 carbon atoms) or multivalentalcohols such as glycols, glycerol, diethylene glycol, pentaerythrit,sorbitol, mannitol, etc., which may optionally also be etherified,esters of citric acid with primary alcohols, acetic acid, urea, benzylbenzoate, dioxolans, glycerol formals, tetrahyxdrofurfuryl alcohol,polyglycol ethers with C₁ -C₁₂ alcohols, dimethylacetamide, lactamides,lactates, ethyl carbonates, silicons (in particular medium-viscouspolydimethylsiloxans), calcium carbonate, sodium carbonate, calciumphosphate, sodium phosphate, magnesium carbonate and the like.

Other auxiliary substances that may be used are those which effect thedisintegration of solid formulations (so-called disintegrants) such as:cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, sodiumcarboxymethyl cellulose or microcrystalline cellulose. It is alsopossible to use known casing substances such as polymerisates as well ascopolymerisates of acrylic acid and/or methacrylic acid and/or estersthereof; copolymerisates of acrylic and methacrylic acid esters with alow ammonium group content (e.g. Eudragit® RS), copolymerisates ofacrylic and methacrylic acid esters and trimethyl ammonium methacrylate(e.g. Eudragit® RL); polyvinylacetate; fats, oils, waxes, fattyalcohols, hydroxypropyl methyl cellulose phthalate or -acetatesuccinate; cellulose acetate phthalate, starch acetate phthalate as wellas polyvinyl acetate phthalate; carboxymethyl cellulose; methylcellulose phthalate, methyl cellulose succinate, - phthalate succinateas well as methyl cellulose-phthalic acid half ester; zein; ethylcellulose as well as ethyl cellulose succinate; shellac, gluten; ethylcarboxyethyl cellulose; ethacrylate-maleic acid anhydride copolymer;styrol-maleic acid copolymerisate; 2-ethylhexyl-acrylate maleic acidanhydride; crotonic acid-vinyl acetate copolymer; glutaminicacid/glutaminic acid ester copolymer; carboxymethyl ethyl-celluloseglycerol monooctanoate; cellulose acetate succinate; polyarginin.

Plasticising agents for casing substances that may be used are:

Citrin and tartaric acid esters (acetyl triethyl citrate, acetyltributyl-, tributyl-, triethyl citrate); glycerol and glycerol esters(glycerol diacetate, -triacetate, acetylated monoglycerides, castoroil); phthalic esters (dibutyl-, diamyl-, diethyl-, dimethyl-,dipropylphthalate), di-(2-methoxy- or 2-ethoxyethyl)-phtalate,ethylphthalyl glycolate, butylphthalyl ethylglycolate andbutylglycolate; alcohols (propylene glycol, polyethylene glycol ofvarious chain lengths), adipates (diethyladipate, di-(2-methoxy or2-ethoxyethyl)-adipate); benzophenon; diethyl- and dibutyl sebacate,dibutyl succinate, dibutyltartrate; diethylene glycol dipropionate;ethylene glycol diacetate, -dibutyrate, -dipropionate; tributylphosphate, tributyrin; polyethylene glycol sorbitan monooleate(polysorbates such as polysorbate 80); sorbitan monooleate.

To prepare solutions or suspensions it is for example possible to usewater or physiologically acceptable organic solvents, such as forexample alcohols (ethanol, propanol, isopropanol, 1,2-propylene glycol,polyglycols and derivatives thereof, fatty alcohols, partial esters ofglycerol), oils (for example silicon oil, peanut oil, olive oil, sesameoil, almond oil, sunflower oil, soya bean oil, castor oil, cattle hoofoil), paraffins, dimethyl sulfoxide, triglycerides and the like).

For injectable solutions or suspensions it is for example possible touse non-toxic parenterally acceptable diluents or solvents, such as forexample: water, 1,3-butane diol, ethanol, 1,2-propylene glycol,polyglycols mixed with water, glycerol, Ringer's solution, isotonic saltsolution or also solidified oils including synthetic mono- ordiglycerides or fatty acids such as oleic acid.

For the preparation of the formulations it is possible to use known andconventional solubilisers or emulsifiers. Solubilisers and emulsifiersthat may for example be used are: polyvinyl pyrrolidone, sorbitan fattyacid esters such as sorbitan trioleate, phosphatids such as lecithin,acacia, tragacanth, polyoxyethylated sorbitan monooleate and otherethoxylated fatty acid esters of sorbitan, polyoxyethylated fats,polyoxyethylated oleotriglycerides, linolisated oleotriglycerides,polyethylene oxide condensation products of fatty alcohols,alkylphenolen or fatty acids or also1-methyl-1-(2-hydroxyethyl)imidazolidon-(2). Polyoxylethylated in thiscontext means that the appropriate substances contain polyoxyethylenechains, the degree of polymerisation of which generally lies between 2to 40 and in particular between 10 to 20. Polyoxyethylated substances ofthis kind may for example be obtained by reaction of hydroxylgroup-containing compounds (for example mono- or diglycerides orunsaturated compounds such as those which contain oleic acid radicals)with ethylene oxide (e.g. 40 Mol ethylene oxide per 1 Mol glyceride).

Examples of oleotriglycerides are olive oil, peanut oily castor oil,sesame oil, cottonseed oil, corn oil.

The daily doses in the use according to the invention are 0.01 to 800mg, preferably 0.1 to 600 mg and in particular 0.2 to 200 mgdihydrolipoic acid in the form of the racemate.

The maximum daily dosage should not exceed 800 mg. The daily doses maybe used in the form of a single administration of the entire amount orin the form of 1 to 6, in particular 1 to 4 partial doses per day. Ingeneral, administration of from 1 to 4 times, in particular 1 to 3 timesdaily is preferred. The preferred daily dose for the dihydrolipoic acidis for example 80 mg for the parenteral form of application and 200 mgfor the oral form. In particular the daily dose for the parenteralapplication form is 50 mg and 150 mg for the oral form.

Use may also be as a systemic (oral, parenteral), administeredmedicament.

Dihydrolipoic acid may in particular also be applied in the form of asolution, for example peroral, topical, parenteral (intravenous,intra-articular, intramuscular, subcutaneous), inhalative, rectal,transdermal or vaginal, in the vitreous body of the eye, intra-ocular inthe anterior eye chamber, or in the conjunctival sac of the eye.

Medicaments containing dihydrolipoic acid as active substance may, forexample, be formulated in the form of tablets, capsules, pills or coatedtablets, granulates, suppositories, pellets, plasters, solutions oremulsions, the active substance being combined with appropriateauxiliary substances and carriers. In the case of solutions, thesecontain for example 0.5 to 20% by weight, preferably 1 to 10% by weightof dihydrolipoic acid.

The dosage unit of the medicament containing dihydrolipoic acid or atherapeutically applicable salt thereof may, for example, contain:

a) in the case of peroral medicinal forms: 10 to 800 mg, preferably 20to 600 mg, in particular 20 to 200 mg dihydrolipoic acid. The doses mayfor example be given 1 to 6, preferably 1 to 4, in particular 1 to 3times daily. A total dose of 800 mg per day should, however, not beexceeded. The same applies to the following medicinal forms listed underb) to e).

b) in the case of parenteral medicinal forms (e.g. intra-ocular orintravenous, intramuscular or intra-articular): 0.01 to 300 mg,preferably 0.15 to 200 mg, in particular 1 to 100 mg dihydrolipoic acid.The doses may for example be given 1 to 6, preferably 1 to 4, inparticular 1 to 3 times daily.

c) in the case of medicinal forms for rectal or vaginal application: 10to 500 mg, preferably 20 to 400, in particular 30 to 200 mgdihydrolipoic acid: The doses may for example be given 1 to 6,preferably 1 to 4, in particular 1 to 3 times daily.

d) in the case of medicinal forms for application to the skin and mucousmembranes, conjunctival sac or intra-ocular (e.g. as solutions, lotions,emulsions, ointments, plasters, etc.): 0.01 to 800 mg dihydrolipoicacid, preferably 0.1 to 250 mg, in particular 0.2 to 200 mgdihydrolipoic acid. The doses may for example be given 1 to 6,preferably 1 to 4, in particular 1 to 3 times daily.

It is of course also possible to prepare galenic formulations whichcontain the above dosage units 2 to for example 10 times. In particularcapsules contains 20 to 600 mg, pellets or granulates 20 to 400 mg,suppositories 20 to 300 mg dihydrolipoic acid.

The above-cited weight amounts refer in each case to pure dihydrolipoicacid, i.e. not to the salts. If salts are used, the dose amounts mustcorrespond in each case and be appropriately increased according to thechanged molecular weight.

It is for example possible to use for oral application:

1) Dihydrolipoic acid or a pharmaceutically acceptable salt ofdihydrolipoic acid, together with conventional carriers and/or diluentsand/or auxiliary substances mixed and/or homogenised and optionally castthe mixture so obtained into hollow cells of appropriate size or fillinto capsules of appropriate size or granulate and then optionally pressinto tablets with the addition of other conventional auxiliarysubstances or fill into capsules containing in the dosage unit 0.01 to800 mg dihydrolipoic acid or a pharmaceutically acceptable salt ofdihydrolipoic acid. The preparation of this formulation occurs attemperatures between 0° and 120° C., preferably 20° to 80° C.

2) Dihydrolipoic acid or a pharmaceutically acceptable salt ofdihydrolipoic acid, optionally with an antioxidant as well as optionallyone or several of the following substances: starch, cyclodextrin, urea,cellulose, lactose, formalin-casein, modified starch, magnesiumstearate, calcium hydrogen phosphate, silicic acid, optionallygranulates the mixture obtained with an aqueous solution which containsas constituent at least gelatin, starch, polyvinyl pyrrolidone, vinylpyrrolidone-vinyl acetate copolymerisate and/or polyoxyethylene sorbitanmonooleate, optionally homogenises the granulate with one or several ofthe above-mentioned auxiliary substances, and presses this mixture intotablets or fills it into capsules, the tablets or capsules containing inthe dosage unit in each case 0.01 to 800 mg active substancedihydrolipoic acid or a salt thereof. This formulation is prepared attemperatures between 0° and 120° C., preferably 20° to 80° C.

For topical application it is for example possible to use:

1) Dihydrolipoic acid or a pharmaceutically acceptable salt ofdihydrolipoic acid, optionally with 0.001 to 1 part by weight (relatedto 1 part by weight of dihydrolipoic acid) antioxidant as well asoptionally with addition of one or several emulsifiers and/or complexformers with at least one of the following substances to a mixturecontaining 0.5 to 20 percent by weight of dihydrolipoic acid,homogenized and optionally emulsified: water, glycerin, paraffin,Vaseline, aliphatic alcohol with 12 to 25 carbon atoms, aliphaticmonocarboxylic acid with 15 to 20 carbon atoms, sorbitan monopalmitate,polyoxyethylene polyol fatty acid ester, mono- or multivalent lowermolecular aliphatic alcohol, fatty acid glyceride, wax, silicon,polyethylene glycol, polyethylene oxide. This formulation is prepared attemperatures between 20° and 120° C.

It is of course possible to add polyphenols such as rutin, quercitin ormorin or mixtures thereof or a pharmaceutically applicable salt.

2) Dihydrolipoic acid or a pharmaceutically acceptable salt ofdihydrolipoic acid optionally with 0.001 to 1 part by weight (related to1 part by weight of dihydrolipoic acid) antioxidant as well asoptionally with addition of a complex former and/or an emulsifier water,physiologically acceptable alcohols, dimethyl sulfoxide, polyethyleneglycol or oils or mixtures thereof and optionally fills the solutionso-obtained with as much water, alcohol, dimethyl sulfoxide,polyethylene glycol or oil so that the final solution, final suspensionor final emulsion contains 0-5-20 percent by weight of active substancedihydrolipoic acid. This formation is prepared at temperatures between30° and 100° C. It is of course possible to add polyphenols such asrutin, quercetin or morin or mixtures thereof or a pharmaceuticallyacceptable salt.

3) Cream containing 10% dihydrolipoic acid

50 g polyoxyethylene-40-stearate (trade name.: Myrj®52), 80 g cetylstearyl alcohol, 200 g white Vaseline, 50 g viscous paraffin and 5 gdimethicone are melted together in a homogenising apparatus. 1.26 gmethyl-4-hydroxybenzoate and 0.533 g propyl-4-hydroxybenzoate aredissolved in the melt.

1.4 g methyl-4-hydroxybenzoate and 0.6 g propyl-4-hydroxybenzoate aredissolved in 511.207 g purified water at 70° C. The solution isemulsified into the above-obtained fat melt. The emulsion is homogenisedand cooled to room temperature with stirring. 100 g dihydrolipoic acidare then stirred into the cream and homogenised again in a vacuum.

4) Eye drops with 0.01 to 25 mmol dihydrolipoic acid as racemate

To prepare eye drops it is preferred to add preservatives, lubricantsand effective wetting agents to the preparation.

Preservatives that may for example be used are benzalkonium chlorideswhich have an antiseptic and surface-active effect. It is also preferredto add glycerin and physiological salt solution to the eye drops.

For 100 ml eye drops

    ______________________________________                                        Dihydrolipoic acid 0.01 to 25 mmol                                            ______________________________________                                        H.sub.2 NaPO.sub.4.H.sub.2 O                                                                         0.018 g                                                HNa.sub.2 PO.sub.4.12 H.sub.2 O                                                                      0.190 g                                                glycerin and/or dextran                                                                              0.100 g                                                sterile water up to    100 ml                                                 ______________________________________                                    

Stabilizers, preservatives in adequate amount.

Topical use is effected dropwise directly into the eye. The frequency ofapplication varies from once to five times daily. Another mode of useconsists in applying the above-described formulation to the eye via acarrier. Suitable carriers are keratin disks or soft contact lenseswhich are applied after pre-incubation. Alternatively, liposomepreparations may also be added to the eye drops for direct applicationor application via a carrier.

I claim:
 1. A method of suppressing or reducing an intolerance reactionresulting from an implant or endoprosthesis comprisingcontacting an areaof living tissue in contact with or near the implant or endoprosthesiswith an effective amount of a pharmaceutical composition comprisingdihydrolipoic acid, or a physiologically acceptable salt ofdihydrolipoic acid, or mixture thereof such that the intolerancereaction is suppressed or reduced.
 2. The method according to claim 1wherein the intolerance reaction is associated with a region of or nearan eye.
 3. The method according to claim 1 wherein the implant is anophthalmological implant.
 4. The method according to claim 1 wherein thearea of living tissue is contacted with the pharmaceutical compositionbefore the intolerance reaction develops.
 5. The method according toclaim 1 wherein the pharmaceutical composition comprises a racemicmixture of R- or S-dihydrolipoic acid.
 6. The method according to claim1 wherein the pharmaceutical composition comprises an enantiomericallypure form of dihydrolipoic acid.
 7. The method according to claim 1wherein the pharmaceutical composition further comprises polyphenol. 8.The method according to claim 7 wherein the polyphenol is selected fromthe group consisting of rutin, quercetin, morin, and mixtures thereof.